The koff values of ligands unbinding to proteins are key parameters for drug discovery. Their predictions based on molecular simulation may under- or overestimate experiment in a system- and/or technique-dependent way. Here we use an established method-infrequent metadynamics, based on the AMBER force field-to compute the koff of the ligand iperoxo (in clinical use) targeting the muscarinic receptor M2. The ligand charges are calculated by either (i) the Amber standard procedure or (ii) B3LYP-DFT. The calculations using (i) turn out not to provide a reasonable estimation of the transition-state free energy. Those using (ii) differ from experiment by 2 orders of magnitude. On the basis of B3LYP DFT QM/MM simulations, we suggest that the observed discrepancy in (ii) arises, at least in part, from the lack of electronic polarization and/or charge transfer in biomolecular force fields. These issues might be present in other systems, such as DNA-protein complexes.
Accuracy of Molecular Simulation-Based Predictions of koff Values: A Metadynamics Study / Capelli, R.; Lyu, W.; Bolnykh, V.; Meloni, S.; Olsen, J. M. H.; Rothlisberger, U.; Parrinello, M.; Carloni, P.. - In: THE JOURNAL OF PHYSICAL CHEMISTRY LETTERS. - ISSN 1948-7185. - 11:15(2020), pp. 6373-6381.
Titolo: | Accuracy of Molecular Simulation-Based Predictions of koff Values: A Metadynamics Study |
Autori: | |
Data di pubblicazione: | 2020 |
Rivista: | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1021/acs.jpclett.0c00999 |
Appare nelle tipologie: | 1.1 Articolo in rivista |
File in questo prodotto:
File | Descrizione | Tipologia | Licenza | |
---|---|---|---|---|
receptor.pdf | Main Text | 2a Post-print versione editoriale / Version of Record | Non Pubblico - Accesso privato/ristretto | Administrator Richiedi una copia |
jz0c00999_si_001.pdf | Supporting information (pdf) | Altro materiale allegato | Non Pubblico - Accesso privato/ristretto | Administrator Richiedi una copia |
LaTeX_JPCLetters-2.pdf | Ultima versione sottomessa e accettata per la pubblicazione | 2. Post-print / Author's Accepted Manuscript | PUBBLICO - Tutti i diritti riservati | Embargo: 16/07/2021 Richiedi una copia |
http://hdl.handle.net/11583/2844573